Lung and esophageal cancer represent common malignancies which cause the death of >180,000 individuals each year in the United States alone. Currently available chemotherapy both as neoadjuvant treatment and as palliative therapy for advanced disease has had a small but measurable effect on the survival of patients with these diseases. However, while a number of different drugs (for example alkylating agents, platinum compounds, 5FU, and taxanes) are available, no means currently exists for selecting therapy based upon the biology of a patient's individual tumor. We have shown, previously, that DNA hypermethylation associated promoter region silencing of the DNA damage repair gene O6-MGMT, can predict patients sensitive to alkylating agents, and these patients benefit with long-term survival. We now have preliminary data in esophageal cancer patients suggesting that hypermethylation of the checkpoint with forkhead and ring finger domains gene (CHFR) detected by Methylation Specific PCR (MSP) correlates with response to therapy with taxanes and results in prolonged survival of individual patients with CHFR methylation. In the R21 portion of this proposal, we intend to (1) complete a single institution, retrospective trial of neoadjuvant taxane-based therapy in esophageal cancer and extend our analysis to lung cancer patients who also have been treated with neoadjuvant taxanes; (2) detect methylation of CHFR in plasma from patients with esophageal cancer to determine if plasma can be used when tumor tissue is not available; (3) determine the performance characteristics of this assay and compare results between gel-based MSP and real-time MSP for the CHFR gene. In the R33 component of this application, we will validate both our gel-based and real-time tests for CHFR methylation in multi-institutional retrospective studies in lung and esophageal cancer. Then, we intend to apply mainly our real-time assay to prospective studies both in single and multi-institutional settings. These studies, for both neoadjuvant and palliative treatments, will determine the clinical utility of CHFR methylation to predict sensitivity of lung and esophageal cancer to taxanes. They may also provide the basis for targeted use of these agents in other cancer types, including colon, gastric, and head and neck cancer, where CHFR methylation is also frequently observed. Taxanes are a class of chemotherapeutic agents widely used to treat lung and esophageal cancer patients, but many patients do not respond to these drugs. We will further develop a test for CHFR methylation and determine whether CHFR methylation can be used to predict which patients will respond to taxane based chemotherapies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33CA127055-02
Application #
7665203
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Lively, Tracy (LUGO)
Project Start
2008-08-01
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$270,600
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Guo, Mingzhou; Alumkal, Joshi; Drachova, Tatiana et al. (2015) CHFR methylation strongly correlates with methylation of DNA damage repair and apoptotic pathway genes in non-small cell lung cancer. Discov Med 19:151-8
Li, Yazhuo; Yang, Yunsheng; Lu, Youyong et al. (2015) Predictive value of CHFR and MLH1 methylation in human gastric cancer. Gastric Cancer 18:280-7
Cleven, Arjen H G; Derks, Sarah; Draht, Muriel X G et al. (2014) CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer. Clin Cancer Res 20:3261-71
Healey, Megan A; Deaton, Staci L; Alder, Jonathan K et al. (2010) Id1 overexpression is independent of repression and epigenetic silencing of tumor suppressor genes in melanoma. Epigenetics 5:410-21
Meguid, Robert A; Hooker, Craig M; Taylor, Joshua T et al. (2009) Recurrence after neoadjuvant chemoradiation and surgery for esophageal cancer: does the pattern of recurrence differ for patients with complete response and those with partial or no response? J Thorac Cardiovasc Surg 138:1309-17